8di4
Discovery of MK-8189, a highly potent and selective PDE10A inhibitor for the treatment of schizophrenia
Structural highlights
FunctionPDE10_HUMAN Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. Can hydrolyze both cAMP and cGMP, but has higher affinity for cAMP and is more efficient with cAMP as substrate.[1] Publication Abstract from PubMedPDE10A is an important regulator of striatal signaling that, when inhibited, can normalize dysfunctional activity. Given the involvement of dysfunctional striatal activity with schizophrenia, PDE10A inhibition represents a potentially novel means for its treatment. With the goal of developing PDE10A inhibitors, early optimization of a fragment hit through rational design led to a series of potent pyrimidine PDE10A inhibitors that required further improvements in physicochemical properties, off-target activities, and pharmacokinetics. Herein we describe the discovery of an isomeric pyrimidine series that addresses the liabilities seen with earlier compounds and resulted in the invention of compound 18 (MK-8189), which is currently in Phase 2b clinical development for the treatment of schizophrenia. Discovery of MK-8189, a Highly Potent and Selective PDE10A Inhibitor for the Treatment of Schizophrenia.,Layton ME, Kern JC, Hartingh TJ, Shipe WD, Raheem I, Kandebo M, Hayes RP, Huszar S, Eddins D, Ma B, Fuerst J, Wollenberg GK, Li J, Fritzen J, McGaughey GB, Uslaner JM, Smith SM, Coleman PJ, Cox CD J Med Chem. 2023 Jan 26;66(2):1157-1171. doi: 10.1021/acs.jmedchem.2c01521. Epub , 2023 Jan 9. PMID:36624931[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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